Expanding the phenotype of children presenting with hypoventilation with biallelic TBCK pathogenic variants and literature review.

Individuals with biallelic TBCK pathogenic variants present in infancy with distinctive facial features, profound hypotonia, severe intellectual impairment and epilepsy. Although rare, it may mimic other neurogenetic disorders leading to extensive investigations. Improved understanding of the clinical phenotype can support early monitoring of complications due to respiratory insufficiency. We present six individuals who were found to have pathogenic biallelic TBCK variants. The clinico-radiological and diagnostic records were reviewed. Five individuals were diagnosed with hypoventilation, requiring respiratory support, highlighting the need for early respiratory surveillance. Characteristic brain imaging in our cohort included periventricular leukomalacia-like changes. We recommend screening for TBCK in hypotonic children with periventricular leukomalacia-like changes, particularly in the absence of prematurity.

Further evidence for attenuated phenotype with variants in the BMPER gene causing DSD: Case report and literature review.

Diaphonospondylodysotosis (DSD) and ischiospinal dysostosis (ISD) are rare skeletal dysplasias with variants in the bone morphogenetic protein-binding endothelial regulator (BMPER). There is a continuum of clinical presentation, with DSD at the severe end of the spectrum whilst ISD is towards the milder end. Both are caused due to pathogenic variants in BMPER. Previous studies have reported 20 patients from 13 families. Common features in the cohort reported so far are spinal and rib anomalies but other findings illustrate phenotypic variation. Survival ranges from death within the neonatal period to alive and well at 19 years. We present three siblings with variable phenotype, adding to the evidence for a single definition of BMPER-related skeletal dysplasia. We highlight the need for ongoing care planning and guarded prognostication, with regular review by clinical teams.

Our health counts: population-based measures of urban Inuit health determinants, health status, and health care access.

OBJECTIVE: Health determinants and outcomes are not well described for the growing population of Inuit living in southern urban areas of Canada despite known and striking health disparities for Inuit living in the north. The objective of this study was to work in partnership with Tungasuvvingat Inuit (TI) to develop population prevalence estimates for key indicators of health, including health determinants, health status outcomes, and health services access for Inuit in Ottawa, Canada. METHODS: We employed community-based respondent driven sampling (RDS) and a comprehensive health assessment survey to collect primary data regarding health determinants, status, and service access. We then linked with datasets held by the Institute for Clinical Evaluative Sciences (ICES), including hospitalization, emergency room, and health screening records. Adjusted population-based prevalence estimates and rates were calculated using custom RDS software. RESULTS: We recruited 341 Inuit adults living in Ottawa. The number of Inuit living, working or accessing health and social services in the City of Ottawa was estimated to be 3361 (95% CI 2309-4959). This population experiences high rates of poverty, unemployment, household crowding, and food insecurity. Prevalence of hypertension (25%; 95% CI 18.1-33.9), chronic obstructive pulmonary disease (6.7%; 95% CI 3.1-10.6), cancer (6.8%; 95% CI 2.7-11.9), and rates of emergency room access were elevated for Inuit in Ottawa compared to the general population. Access to health services was rated fair or poor by 43%. Multiple barriers to health care access were identified. CONCLUSIONS: Urban Inuit experience a heavy burden of adverse health determinants and poor health status outcomes. According to urban Inuit in Ottawa, health services available to Inuit at the time of the study were inadequate.

Low HIV testing among persons who inject drugs-National HIV Behavioral Surveillance, 20 U.S. cities, 2012.

INTRODUCTION: Persons who inject drugs (PWID) continue to be disproportionately affected by HIV. HIV testing is key to reducing HIV transmission by increasing awareness of HIV status and linking HIV-positive persons to care. Using data from PWID participating in CDC's National HIV Behavioral Surveillance (NHBS) system, we examined prevalence of recent HIV testing among PWID by certain characteristics to guide interventions to increase HIV testing. METHODS: We analyzed NHBS data from PWID 18 years or older recruited via respondent-driven sampling in 20 US cities in 2012. We examined demographic and behavioral factors associated with recent HIV testing (within 12 months before interview) using a Poisson model to calculate adjusted prevalence ratios (aPRs). RESULTS: Of 9555 PWID, 53% had recently tested for HIV. In multivariable analysis, HIV testing was more frequent among participants who visited a healthcare provider (aPR 1.50, P<0.001), participated in alcohol or drug treatment (aPR 1.21, P<0.001), or received an HIV prevention intervention (aPR 1.26, P<0.001). HIV testing was also more frequent among participants who received free sterile syringes (aPR 1.12, P<0.001). DISCUSSION: Only half of PWID participating in NHBS in 2012 reported recent HIV testing. HIV testing was more frequent among participants who accessed health and HIV prevention services. To increase HIV testing among PWID, it is important for providers in healthcare and HIV prevention settings to proactively assess risk factors for HIV, including injection drug use, and offer a wide range of appropriate interventions, such as HIV testing.

Factors Associated With Recent Human Immunodeficiency Virus Testing Among Men Who Have Sex With Men in Puerto Rico, National Human Immunodeficiency Virus Behavioral Surveillance System, 2011.

BACKGROUND: Annual human immunodeficiency virus (HIV) testing is considered a key strategy for HIV prevention for men who have sex with men (MSM). In Puerto Rico, HIV research has primarily focused on injection drug use, yet male-to-male sexual transmission has been increasing in recent years. METHODS: Cross-sectional data from the National HIV Behavioral Surveillance system collected in 2011 in San Juan, Puerto Rico, were analyzed to identify factors associated with HIV testing in the past 12 months (recent testing). RESULTS: Overall, 50% of participants were tested recently. In the multivariate analysis, testing recently was associated with having multiple partners in the past 12 months (adjusted prevalence ratio [aPR] [≥4 vs 1 partner] = 1.5; 95% confidence interval [95% CI], 1.2-2.0), visiting a health care provider in the past 12 months (aPR, 1.4; 95% CI, 1.04-1.8), and disclosing male-male attraction/sex to a health care provider (aPR< 1.4; 95% CI, 1.1-1.7). CONCLUSIONS: Human immunodeficiency virus testing was suboptimal among MSM in San Juan. Strategies to increase HIV testing among MSM may include promoting HIV testing for all sexually active MSM including those with fewer partners, increasing utilization of the healthcare system, and improving patient-provider communication.

Mitochondrial Tim9 protects Tim10 from degradation by the protease Yme1.

Translocase of IM (inner membrane; Tim)9 and Tim10 are essential homologue proteins of the mitochondrial intermembrane space (IMS) and form a stable hexameric Tim9-Tim10 complex there. Redox-switch of the four conserved cysteine residues plays a key role during the biogenesis of these proteins and, in turn, the Tim proteins play a vital chaperone-like role during import of mitochondrial membrane proteins. However, the functional mechanism of the small Tim chaperones is far from solved and it is unclear whether the individual proteins play specific roles or the complex functions as a single unit. In the present study, we examined the requirement and role for the individual disulfide bonds of Tim9 on cell viability, complex formation and stability using yeast genetic, biochemical and biophysical methods. Loss of the Tim9 inner disulfide bond led to a temperature-sensitive phenotype and degradation of both Tim9 and Tim10. The growth phenotype could be suppressed by deletion of the mitochondrial i-AAA (ATPases associated with diverse cellular activities) protease Yme1, and this correlates strongly with stabilization of the Tim10 protein regardless of Tim9 levels. Formation of both disulfide bonds is not essential for Tim9 function, but it can facilitate the formation and improve the stability of the hexameric Tim9-Tim10 complex. Furthermore, our results suggest that the primary function of Tim9 is to protect Tim10 from degradation by Yme1 via assembly into the Tim9-Tim10 complex. We propose that Tim10, rather than the hexameric Tim9-Tim10 complex, is the functional form of these proteins.

Folding and biogenesis of mitochondrial small Tim proteins.

Correct and timely folding is critical to the function of all proteins. The importance of this is illustrated in the biogenesis of the mitochondrial intermembrane space (IMS) "small Tim" proteins. Biogenesis of the small Tim proteins is regulated by dedicated systems or pathways, beginning with synthesis in the cytosol and ending with assembly of individually folded proteins into functional complexes in the mitochondrial IMS. The process is mostly centered on regulating the redox states of the conserved cysteine residues: oxidative folding is crucial for protein function in the IMS, but oxidized (disulfide bonded) proteins cannot be imported into mitochondria. How the redox-sensitive small Tim precursor proteins are maintained in a reduced, import-competent form in the cytosol is not well understood. Recent studies suggest that zinc and the cytosolic thioredoxin system play a role in the biogenesis of these proteins. In the IMS, the mitochondrial import and assembly (MIA) pathway catalyzes both import into the IMS and oxidative folding of the small Tim proteins. Finally, assembly of the small Tim complexes is a multistep process driven by electrostatic and hydrophobic interactions; however, the chaperone function of the complex might require destabilization of these interactions to accommodate the substrate. Here, we review how folding of the small Tim proteins is regulated during their biogenesis, from maintenance of the unfolded precursors in the cytosol, to their import, oxidative folding, complex assembly and function in the IMS.

Identification and characterization of mitochondrial Mia40 as an iron-sulfur protein.

Mia40 is a highly conserved mitochondrial protein that plays an essential role in the import and oxidative folding of many proteins of the mitochondrial intermembrane space. Mia40 uses its redox active CPC motif to shuttle disulfides between its client proteins (newly imported proteins) and the thiol oxidase Erv1. As a thiol oxidoreductase, no cofactor was found in Mia40, nor is a cofactor required for this function. In the present study we, for the first time based on both in vitro and in vivo studies, show that yeast Mia40 can exist as an Fe-S (iron-sulfur) protein as well. We show that Mia40 binds a [2Fe-2S] cluster in a dimer form with the cluster co-ordinated by the cysteine residues of the CPC motifs. The biological relevance of the cofactor binding was confirmed in vivo by cysteine redox state and iron uptake analyses, which showed that a significant amount of cellular Mia40 binds iron in vivo. Furthermore, our oxygen consumption results suggested that the Fe-S-containing Mia40 is not an electron donor for Erv1. Thus we conclude that Mia40 is a novel Fe-S protein with a new cluster-binding motif (CPC), and apart from the thiol oxidoreductase activity, Mia40 may have another important, as yet undefined, function in cells.